Download Metabolic Changes during Starvation

Clinical Science and Malecular Medicine (1 975) 49, 1 ~ - 2 9 ~ .
MEDICAL RESEARCH SOCIETY
A meeting of the Medical Research Society was held on Friday and Saturday, 11 and 12 July 1975, at Oxford.
The following Symposium and Communications were presented.
alanine output in prolonged fasting cannot be accounted
for on the basis of alterations in the secretion of insulin,
glucagon, or other gluco-regulatory hormones. Recent
studies, however, indicate that hyperketonaemia may of
itself reduce the output of alanine from muscle and
decrease the rate of protein catabolism. Infusion of 3hydroxybutyric acid in fasting may result in a fall in blood
alanine and a decline in urinary nitrogen excretion. Thus
ketones may have a dual role in the ‘protein-sparing
phase’ of starvation: as a substrate for the brain, and as a
signal to muscle limiting alanine output and protein
catabolism.
SYMPOSIUM: Clinical Disorders of Intermediary
Carbohydrate Metabolism
A. A NEW EFFECT OF METI-IIONINE ON LIVER
METABOLISM
H. A. KREBS
Metabolic Research Laboratory, Nufield Department of
Clinical Medicine, Oxford
B. METABOLIC CHANGES DURING STARVATION
P. FELIG
Clinical Research Centre, Yale University School of
Medicine, New Haven, Connecticut
The metabolic response to starvation may be characterized as biphasic in which an initial or ‘gluconeogenic
phase’ and a delayed or ‘protein-sparing phase’ may be
identified. The early response to starvation is concerned
with the maintenance of adequate glucose release from
the liver so as to meet the on-going needs of the brain.
This is achieved by stimulation of hepatic glycogenolysis
and gluconeogenesis. The hormonal signals responsible
for these adaptive changes are a drop in circulating
insulin and a rise in glucagon. Since cerebral glucose
utilization occurs at a rate of 150 g/day and inasmuch at
liver glycogen stores amount to 70-90 g, it is clear that
glycogenolysis becomes a progressively less important
source of blood glucose as fasting extends beyond 18 h.
On the other hand, augmented peripheral release and
hepatic extraction of glucogenic amino acids, notably
alanine, become progressively more important in the
maintenance of glucose homeostasis. This augmented
rate of gluconeogenesis occurs, however, at the expense
of body protein stores, which undergo dissolution at the
rate of 60-80 g (8-10 g of urinary nitrogen) per day.
As fasting progresses beyond 1 week and extends for
periods of 3-6 weeks, the rate of nitrogen loss declines to
less than 5 g/day. This delayed response may thus be
characterized as ‘protein-sparing’. Since protein-derived
amino acids represent the sole precursors available to
mammalian tissue for de-novo glucose synthesis, a reduction in protein catabolism must be accompanied by a
decline in gluconeogenesis. Glucose homeostasis is maintained in the ‘protein-sparing phase’ via a reduction in
glucose utilization as well as glucose production. During
starvation, ketone acids progressively accumulate in
blood reaching levels of 6-8 mmol/l. In prolonged fasting
ketones are extracted by the brain, thereby reducing
glucose utilization by 60-70%. Hepatic gluconeogenesis
shows a simultaneousdecline of equal magnitude. This is
achieved by means of a reduction in output of glycogenic
amino acids, particularly alanine, from muscle.
These changes in protein catabolism and muscle
C. THE PATHOGENESIS OF DIABETIC KETOACIDOSIS
K. G. M. M. ALBERTI
Faculty of Medicine, Chemical Pathology and Human
Metabolism, Southampton General Hospital, Southampton
SO9 4XY
Severe diabetic ketoacidosis remains a potentially lethal
condition with mortality rates ranging from 5 to 10% in
good centres to 25% elsewhere. Knowledge of the precipitating factors and biochemical genesis of ketoacidosis
should improve prevention, recognition and logical
treatment of the condition.
The major causes and precipitating factors of ketoacidosis are: (1) infection, (2) failure to diagnose new
diabetes, (3) decreased insulin administration, and (4)
other acute disease states such as myocardial infarction,
cerebrovascular accidents and trauma (Hockaday &
Alberti, 1972, Clinics in Endocrinology, 3, 751). Some of
these factors are associated purely with insulin deficiency
but in infection and other acute conditions patients may
be taking their normal insulin dose but still become ketoacidotic. In such states the circulating concentrations of
the ‘stress’ or catabolic hormones are increased and it has
been assumed that this results in a relative insulin deficiency. High plasma concentrations of these catabolic
hormones (glucagon, catecholamines and cortisol) have
frequently been reported in severe diabetic ketoacidosis
but it has not been known whether these are late sequelae
of the condition or are of pathogenic significance.
Recent work has clarified the role of these hormones.
In two separate studies (Mberti, Christensen, Iversen &
Brskov, 1975, h n c e t , in press; Gerich, Tsalikian,
Lorenzi, et al., 1975, Journal of Clinical Endocrinology
and Metabolism, in press) hormonal and metabolic
changes have been measured after insulin withdrawal
from insulin-requiring diabetic patients. Blood glucose
rose rapidly to a plateau while blood ketone body and
plasma FFA concentrations rose more gradually. Plasma
glucagon concentration showed an early rise and correlated strongly with the rise in ketone body concentra1P